Synovial Epstein-Barr virus infection increases the risk of rheumatoid arthritis in individuals with the shared HLA-DR4 epitope

Saal, J. G.; Krimmel, Michael; Steidle, Michael; Gerneth, Friederike; Wagner, Silvia; Fritz, Péter; Koch, Silvia; Zacher, J.; Sell, Stefan; Einsele, Hermann; Müller, Claudia

doi:10.1002/1529-0131(199907)42:7<1485::aid-anr24>3.0.co;2-7

Cited by 91 publications

(48 citation statements)

References 40 publications

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“…Currently, a large body of evidence points toward the involvement of DNA viruses in the pathogenesis of RA. In the synovial tissue of RA patients, parvovirus B19, Epstein-Barr virus, and cytomegalovirus were found to be frequently present (3,4,7,(42)(43)(44)(45). Although not fully investigated, it is also very likely that RNA viruses occur in the synovial compartment.…”

Section: Discussionmentioning

confidence: 99%

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Roelofs¹,

Joosten²,

Abdollahi‐Roodsaz³

et al. 2005

Arthritis & Rheumatism

294

219

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Objective. To evaluate the expression of Toll-like receptors (TLRs) 3 and 7 in synovium and to study potential differences in the maturation and cytokine production mediated by TLR-2, TLR-3, TLR-4, and TLR-7/8 by dendritic cells (DCs) from rheumatoid arthritis (RA) patients and DCs from healthy controls.Methods. Synovial expression of TLR-3 and TLR-7 in RA was studied using immunohistochemistry. Monocyte-derived DCs from RA patients and healthy controls were cultured for 6 days and subsequently stimulated for 48 hours via TLR-mediated pathways (lipoteichoic acid, Pam 3 Cys, and fibroblast-stimulating lipopeptide 1 for TLR-2, poly[I-C] for TLR-3, lipopolysaccharide and extra domain A for TLR-4, and R848 for TLR-7/8). Phenotypic DC maturation was measured using flow cytometry. The secretion of tumor necrosis factor ␣ (TNF␣), interleukin-6 (IL-6), IL-10, and IL-12 was measured using the Bio-Plex system. Cell lines expressing TLR-2 and TLR-4 were used for the detection of TLR-2 and TLR-4 ligands in serum and synovial fluid from RA patients.Results. TLR-3 and TLR-7 were highly expressed in RA synovium. All TLR ligands elicited phenotypic DC maturation equally between DCs from RA patients and those from healthy controls. TLR-2-and TLR-4-mediated stimulation of DCs from RA patients resulted in markedly higher production of inflammatory mediators (TNF␣ and IL-6) compared with DCs from healthy controls. In contrast, upon stimulation of TLR-3 and TLR-7/8, the level of cytokine production was equal between DCs from RA patients and those from healthy controls. Remarkably, both TLR-3 and TLR-7/8 stimulation resulted in a skewed balance toward IL-12. Intriguingly, the combined stimulation of TLR-4 and TLR-3-7/8 resulted in a marked synergy with respect to the production of inflammatory mediators. As a proof of concept, TLR-4 ligands were increased in the serum and synovial fluid of RA patients.Conclusion. TLRs are involved in the regulation of DC activation and cytokine production. We hypothesize that various TLR ligands in the joint trigger multiple TLRs simultaneously, favoring the breakthrough of tolerance in RA.

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Section: Discussionmentioning

confidence: 99%

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Roelofs¹,

Joosten²,

Abdollahi‐Roodsaz³

et al. 2005

Arthritis & Rheumatism

294

219

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“…Furthermore, EBV DNA and RNA were detected in 34% of patients with rheumatoid arthritis compared with 10% of healthy individuals 35 .…”

Section: The Link Between Pamps and Autoimmunitymentioning

confidence: 99%

TLR-dependent T cell activation in autoimmunity

2011

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Autoimmune disease can develop as a result of a breakdown in immunological tolerance, leading to the activation of self-reactive T cells. There is an established link between infection and human autoimmune diseases. Furthermore, experimental autoimmune diseases can be induced by immunization with autoantigens that are administered together with complete Freund's adjuvant containing killed Mycobacteria tuberculosis, which in some cases can be replaced with individual pathogen-associated molecular patterns (PAMPs). Exogenous PAMPs and endogenous danger signals from necrotic cells bind to pathogen recognition receptors, including Toll-like receptors, and activate signaling pathways in innate immune cells and on T cells, leading to inflammatory cytokine production and T cell activation, and this is now considered to be a major factor in the development of autoimmunity.

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“…TLR ligands of microbial origin, such as bacterial DNA and peptidoglycans as well as Epstein-Barr virus, cytomegalovirus, and parvovirus, have repeatedly been found in joints of patients with RA, and several investigators have implicated bacterial or viral infections as initiating factors of the disease (20)(21)(22)(23)(24). In addition, the presence of endogenous TLR ligands such as fibronectin fragments and heat shock proteins, mainly activating TLR4 has been demonstrated in rheumatoid synovium (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis

Abdollahi‐Roodsaz¹,

Joosten²,

Koenders³

et al. 2008

J. Clin. Invest.

473

418

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TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or hostderived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist-knockout (IL1rn -/-) mice, which spontaneously develop an autoimmune T cell-mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn -/-Tlr2 -/-mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-γ production by T cells. IL1rn -/-Tlr4 -/-mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis.

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Synovial Epstein-Barr virus infection increases the risk of rheumatoid arthritis in individuals with the shared HLA-DR4 epitope

Abstract: EBV seems to function as an environmental risk factor for RA, particularly in patients with the RA-linked HLA-DRB1 alleles.

Cited by 91 publications

References 40 publications

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

TLR-dependent T cell activation in autoimmunity

Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis

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